1. Field of the Invention
This invention relates generally to methods for therapy of urogenital disease, and more particularly concerns methods for blocking N-methyl-D-aspartate receptors in urogenital organs, utilizing the response of these tissues to blockers of these receptors, and novel therapeutic uses for these drugs.
2. Description of Related Art
Prostate cancer is one of the most prevalent pathologies in men over 50 years of age and the most common internal cancer of males in the USA. Approximately 140,000 cases are newly diagnosed and about 30,000 die from the disease annually. Radical prostatectomy is the only treatment available to remove the malignant organ, while surgical or chemical androgen ablation is used to avoid or delay the onset of extraprostatic disease. The failure of surgical or medical treatment of prostate cancer is mostly due to the establishment of extraprostatic progression or metastasis, and the parallel progression of the tumor from androgen dependency to androgen unresponsiveness. As a result, androgen ablation fails to stop tumor growth and its spread. Treatment with chemotherapy or other types of drugs is not effective.
Benign prostatic hyperplasia (BPH), an abnormal non-malignant growth of the prostate leading to voiding obstruction and potential bladder instability, also afflicts 50% of men over the age of 50, and is one of the primary causes of hospitalization and surgical procedures in men. Transurethral resection ablation of the prostate (TURP) is one of the most common surgical procedures performed in the USA. The main clinical symptoms are obstructive in nature (decrease force of strain, hesitancy, incomplete voiding) as well as irritative (frequency, urgency, dysuria, nocturia). This is due to partial occlusion of the prostatic urethra by the enlarged prostate, combined with an increase in the tone (contraction) of the prostatic smooth muscle, and in certain cases hypertrophy of the bladder muscle (detrusor). Medical treatment of BPH is based on mainly drugs affecting either prostate growth or tone, with efficacy limited to a fraction of patients and undesirable side effects.
Bladder instability due to involuntary contractile episodes of the detrusor muscle, leading to urge incontinence without stress incontinence, is very common in the elderly population, particularly women. Bladder hyperreflexia due to neurological lesions is also common in this patient population. Both types of disorders may be treated medically with relaxants of the detrusor that facilitate urine storage. However, the drugs are effective in less than one third of patients and often at the cost of substantial side effects.
Erectile dysfunction, which is the impairment of penile smooth muscle relaxation impeding the rigidity necessary for penetration during sexual intercourse, is responsible for most clinically diagnosed cases of impotence (12-15 million men in the US). Organic impotence is associated with vascular disease, diabetes, hypertension, and aging. In the adult onset, insulin-independent type II diabetes mellitus, about 2 million men are assumed to suffer from organic impotence. Erectile dysfunction leads to impotence in up to 75% of adult patients with over 5 years of types I or II diabetes. The incidence of impotence risk factors increases with aging, and in healthy elderly men it may be due to loss of compliance of the penile smooth muscle unrelated to clinically defined vasculopathy or neuropathy. Current medical treatment is based on the delivery into the corpora cavernosa of vasoactive substances that relax the corporal smooth muscle, such as cGMP phosphodiesterase inhibitors, adenylate cyclase stimulators, or alpha-adrenergic blockers. This therapy is not curative and may have side effects for some patients, mainly mild pain, priapism, and corporal fibrosis.
The excitatory amino acids (EAA), L-glutamate, L aspartate, and other related metabolites, exert their neurotransmission effects by acting on receptors located on virtually all neurons in the central nervous system. These receptors, designated with the generic name of glutamate receptors belong to two categories: a) ionotropic, that are directly coupled to membrane sodium or calcium channels; and b) metabotropic, that are coupled with G proteins triggering the arachidonic acid cascade and changes in cAMP.
The N-methyl-D-aspartate receptors (NMDAR) are designated as such because they bind the synthetic aspartate analog N-methyl-D-aspartate (NMDA) and belong to the ionotropic receptors class together with the non-NMDAR (kainate and AMPA receptors). The NMDAR have been identified directly so far only in postsynaptic neurons in the brain and lung tissues, although because of the effects of some NMDAR blockers on the relaxation of arteries and smooth muscle it may be inferred they may be present in other locations. By glutamate orNMDA binding these receptors trigger a Ca2+ influx into the cells that activates a series of Ca2+ dependent cascades, among them nitric oxide synthase (NOS), the enzyme that synthesizes nitric oxide (NO), a pleiotropic neurotransmitter and physiological mediator. NO produced by EAA binding to NMDAR may have dual effects according to its concentration and tissue location. At small doses NO may either diffuse to presynaptic neurons and act as a retrograde messenger, or presumably to blood vessel smooth muscle causing vasodilation. In contrast, at very high doses the NMDAR- triggered NO can induce cytotoxicity, as is further explained below.
The EAA/NMDAR interaction also affects the hypothalamic control of LH pulses and GnRH release in rats in a sex-dependent and presumably NO-mediated manner. This indicates that some of the actions of NMDAR blockers can involve the hypothalamic axis. In addition, EAA/NMDAR can stimulate the release of growth factors and elicit the expression of c-fos protein, a critical step in the early stages of cell proliferation. There are no publications on whether NMDARs play a role in cancer growth or progression in general. MK-801 (noncompetitive, high affinity) and other NMDA blockers have been extensively studied as neuro-protective agents in the treatment of stroke, epilepsy, pain, Parkinson's disease, etc. Many of them are in clinical use and their safety is well evaluated.
Demonstration of NMDARs in the urogenital system has not been previously reported, with isolated exceptions (e.g., indirect evidence on lung and skeletal muscle), outside the central nervous system. The prevalent view is that prostatic tone is controlled mainly by alpha adrenergic receptors, whereas cholinergic and adrenergic pathways regulate bladder tone. The nitric oxide-dependent NANC neurotransmission is not known to be very significant in the prostate, and it is controversial in the case of the bladder, as assessed by organ bath studies. Therefore, the most efficient drugs available in the clinic for prostate and bladder relaxation have been the alpha-adrenergic blockers and anticholinergic agents, respectively.
Recent reports indicated that the NMDAR blocker MK-801 has been tested in rats (intravenously or intrathecally), resulting in an inhibition of bladder contractions in a dose dependent manner, and the investigators have assumed that both AMPA/kainate and NMDA glutamate receptors are important in the micturition reflex pathway. However, these effects have been ascribed exclusively to the spinal cord, and no inference has been made to the presence of these receptors in either the bladder or the prostate.
It would be desirable to provide therapy for urogenital disease utilizing NMDARs that are present in the bladder and prostate to contribute to the tone of these organs, and to utilize NMDAR antagonists to relax the smooth muscle of both bladder and prostate, and presumably the urethra.
Penile tone can also be controlled physiologically by the balance of relaxing and contractile agents. Among the former group, NO is considered to be the mediator of the erectile response through the stimulation of the intracavernosal synthesis of CGMP that leads to the decrease in intracellular Ca2+ and smooth muscle relaxation. However, ancillary pathways causing a similar mobilization of intracellular Ca2+ can operate in the corpora cavernosa. It would therefore be desirable to provide therapies utilizing NMDARs that are present and active in the penis, to elicit a Ca2+ influx, and NMDAR blockers to cause corporal smooth muscle relaxation.
Studies on the central nervous system suggest the opposite view, however, that excitatory amino acids in vivo would cause corporal relaxation through their effects on spinal NMDA receptors, based on experiments showing that MK-801 decreases the erectile response in the anesthetized rat. However, this is opposite to the well established effects of NMDA receptors on Ca2+ channels, and if confirmed would suggest an indirect mechanism on the smooth muscle triggered by spinal NMDA receptors centrally acting on other pathways. The observed effects on the erectile response have been ascribed generally exclusively to the spinal cord.
It would be desirable to provide novel methods of treatment and compounds for the treatment of prostate cancer, benign prostatic hyperplasia, bladder dysfunction in both men and women, erectile dysfunction, and other urogenital disease. Compounds are needed that affect at least the prostate, bladder, and/or the penile corpora cavemosa, and at least in the case of one of them, act simultaneously on the muscle tone and tissue growth (prostate), and there is a need for agents that are safe, with tolerable side-effects. The present invention meets these needs.